Sistema de Salut de Catalunya
Institut Català de la Salut
[Lucas-Del-Pozo S, Fierli F, Koletsi S] Department of Clinical and Movement Neurosciences, UCL Queen Square Institute of Neurology, London, UK. Aligning Science Across Parkinson's (ASAP) Collaborative Research Network, Chevy Chase, MD, USA. [Uras G] Department of Clinical and Movement Neurosciences, UCL Queen Square Institute of Neurology, London, UK. Aligning Science Across Parkinson's (ASAP) Collaborative Research Network, Chevy Chase, MD, USA. Department of Biomedical Science, University of Sassari, Viale San Pietro, Sassari, Italy. [Lentini V] Department of Clinical and Movement Neurosciences, UCL Queen Square Institute of Neurology, London, UK. Department of Biomedical Science, University of Sassari, Viale San Pietro, Sassari, Italy. [Lazaro-Hernandez C] Department of Clinical and Movement Neurosciences, UCL Queen Square Institute of Neurology, London, UK. Servei de Neurologia, Vall d'Hebron Hospital Universitari, Barcelona, Spain
Vall d'Hebron Barcelona Hospital Campus
2025-10-30T08:42:59Z
2025-10-30T08:42:59Z
2025-10-15
Alpha-synuclein; PIKfyve; Parkinson's disease
Alfa-sinucleína; PIKfyve; Enfermedad de Parkinson
Alfa-sinucleïna; PIKfyve; Malaltia de Parkinson
Objective Parkinson's disease (PD) pathophysiology is associated with a progressive loss of dopaminergic neurons in the substantia nigra and accumulation of insoluble inclusions of misfolded alpha-synuclein. In this study, we used a neuroblastoma-derived cell model overexpressing a pro-aggregation form of alpha-synuclein and human-derived induced-pluripotent stem cells (iPSCs) to investigate the efficacy of PIKfyve-mediated lysosomal biogenesis to reduce alpha-synuclein inclusions. Methods We used high-content imaging and enzymatic assays to follow the progression of lysosomal biogenesis, lysosomal catabolism and alpha-synuclein accumulation. The cell models used recapitulated important elements of the biochemical phenotype observed in PD dopaminergic neurons, including alpha-synuclein inclusions and impaired glucocerebrosidase. Results PIKfyve inhibition by YM201636 resulted in a lysosomal-dependant reduction of alpha-synuclein inclusions as early as 24 h post-treatment. YM201636 induced an increase in nuclear translocation of TFEB, and an increase in lysosomal markers LAMP1 and HEXA. PIKfyve-inhibition was also tested in neuronal-differentiated neuroblastoma-derived cells and iPSCs-derived dopaminergic neurons. In these cells, YM201636 substantially reduced alpha-synuclein inclusions and increased TFEB nuclear localisation. Conclusion These findings suggest that PIKfyve signalling pathways could represent a therapeutic target to reduce alpha-synuclein in PD.
This research was funded by Aligning Science Across Parkinson's [Grant number: ASAP000420] through the Michael J. Fox Foundation for Parkinson's Research. For the purpose of open access, the author has applied a CC BY 4.0 public copyright license to all Author Accepted Manuscripts arising from this submission.
Artículo
Versión publicada
Inglés
Neurones dopaminèrgiques; Parkinson, Malaltia de; Inhibidors enzimàtics; DISEASES::Nervous System Diseases::Central Nervous System Diseases::Brain Diseases::Basal Ganglia Diseases::Parkinsonian Disorders::Parkinson Disease; CHEMICALS AND DRUGS::Amino Acids, Peptides, and Proteins::Proteins::Nerve Tissue Proteins::Synucleins::alpha-Synuclein; ANATOMY::Nervous System::Neurons::Dopaminergic Neurons; CHEMICALS AND DRUGS::Chemical Actions and Uses::Pharmacologic Actions::Molecular Mechanisms of Pharmacological Action::Enzyme Inhibitors; ENFERMEDADES::enfermedades del sistema nervioso::enfermedades del sistema nervioso central::enfermedades cerebrales::enfermedades de los ganglios basales::trastornos parkinsonianos::enfermedad de Parkinson; COMPUESTOS QUÍMICOS Y DROGAS::aminoácidos, péptidos y proteínas::proteínas::proteínas del tejido nervioso::sinucleínas::alfa-sinucleína; ANATOMÍA::sistema nervioso::neuronas::neuronas dopaminérgicas; COMPUESTOS QUÍMICOS Y DROGAS::acciones y usos químicos::acciones farmacológicas::mecanismos moleculares de acción farmacológica::inhibidores enzimáticos
Elsevier
Neurobiology of Disease;215
https://doi.org/10.1016/j.nbd.2025.107053
Attribution 4.0 International
http://creativecommons.org/licenses/by/4.0/
Articles científics - HVH [3396]
